Heterocyclic compounds and their preparation and use

ABSTRACT

The present invention relates to therapeutically active azacyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer&#39;s disease, severe painful conditions and glaucoma.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of co-pending applicationSer. No. 08/362,031, filed Dec. 22, 1994 now U.S. Pat. No. 5,571,826,which is a divisional of application Ser. No. 08/026,708, filed Mar. 5,1993 now U.S. Pat. No. 5,376,668, which is a CIP of application Ser. No.07/745,033 filed Sep. 14, 1991, now U.S. Pat. No. 5,328,924.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to therapeutically active azacycliccompounds, a method of preparing the same and to pharmaceuticalcompositions comprising the compounds.

The novel compounds are useful as stimulants of the cognitive functionof the forebrain and hippocampus of mammals and especially in thetreatment of Alzheimer's disease.

2. Description of Related Art

Due to the in general improved health situation in the western world,elderly-related diseases are much more common now than in the past andare likely to be even more common in the future.

One of the elderly-related symptoms is a reduction of the cognitivefunctions. This symptom is especially pronounced in thepathophysiological disease known as Alzheimer's disease. This disease iscombined with, and also most likely caused by, a up to 90% degenerationof the muscarinic cholinergic neurons in nucleus basalis, which is partof substantia innominata. These neurons project to the prefrontal cortexand hippocampus and have a general stimulatory effect on the cognitivefunctions of the forebrain as well as of hippocampus, namely learning,association, consolidation and recognition.

It is a characteristic of Alzheimer's disease that although thecholinergic neurons degenerate, the postsynaptic muscarinic receptors inthe forebrain and hippocampus still exist. Therefore muscariniccholinergic agonists are useful in the treatment of Alzheimer's diseaseand in improving the cognitive functions of elderly people.

It is well known that arecoline (methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate) is such a cholinergicagonist.

Arecoline however has a very short biological half life and a smallseparation between central and peripheral muscarinic effects.Furthermore arecoline is a rather toxic compound.

EP-A-0307142 discloses a class of thiadiazoles, substituted on one ofthe ring carbon atoms with a non-aromatic azacyclic or azabicyclic ringsystem, and substituted on the other ring carbon atom with a substituentof low lipophilicity, or a hydrocarbon substituent, which are muscarinicagonists and therefore useful in the treatment of neurological andmental illnesses and severe painful conditions.

It is an object of the invention to provide new muscarinic cholinergiccompounds.

SUMMARY OF THE INVENTION

The novel compounds of the invention are heterocyclic compounds havingthe formula I ##STR1## wherein Z¹ is oxygen or sulphur;

R is --Z² R², --SOR², --SO₂ R², --Z² --R² --Z³ R³, --Z² --R² --CO--R³,--Z² --R² --CO₂ --R³, --Z² --R² --O₂ C--R³, --Z² --R² --CONH--R³, --Z²--R² --NHCO--R³, --Z² --R² --X, Z² --R² --Z³ --X wherein Z² and Z³independently are oxygen or sulphur, and R² and R³ independently arestraight or branched C₁₋₁₅ -alkyl, straight or branched C₂₋₁₅ -alkenyl,straight or branched C₂₋₁₅ -alkynyl, each of which is optionallysubstituted with halogen, --OH, --CN, --CF₃, one or two phenyl, phenoxy,benzoyl, or benzyloxycarbonyl groups wherein each aromatic group isoptionally substituted with halogen, --CN, C₁₋₄ -alkyl or C₁₋₄ -alkoxy,wherein X is a 5 or 6 membered heterocyclic group containing one to fourN, O or S atoms) or a combination thereof, which heterocyclic group isoptionally which heterocyclic group is optionally substituted at acarbon or nitrogen atom with straight or branched C₁₋₆ -alkyl, phenyl,benzyl or pyridine, or a carbon atom in the heterocyclic group togetherwith an oxygen atom form a carbonyl group, or which heterocyclic groupis optionally fused with a phenyl group; and

R¹ is hydrogen, straight or branched C₁₋₅ -alkyl, straight or branchedC₂₋₅ -alkenyl or straight or branched C₂₋₅ -alkynyl; or

a pharmaceutically acceptable salt thereof.

Examples of such salts include inorganic and organic acid addition saltssuch as hydrochloride, hydrobromide, sulphate, phosphate, acetate,fumarate, maleate, citrate, lactate, tartrate, oxalate, or similarpharmaceutically acceptable inorganic or organic acid addition salt.

The compounds of this invention are also useful analgesic agents andtherefore useful in the treatment of severe painful conditions.

Furthermore, the compounds of this invention are useful in the treatmentof glaucoma.

The invention also relates to methods of preparing the above mentionedcompounds, comprising:

a) alkylating a compound of formula II ##STR2## wherein Z² and R havethe meaning defined above with an alkyl halide and reducing the compoundthus formed with hydride ions to form a compound of formula I ##STR3##wherein Z¹, Z², R and R¹ have the meanings defined above, or

b) oxidizing a compound of formula III ##STR4## wherein Z², R¹ and R²have the meanings defined above by standard procedures to form acompound of formula IV ##STR5## and subsequent displacement of --SO₂ R²with an appropriate nucleophile to form a compound of formula I.

It is to be understood that the invention extends to each of thestereoisomeric forms of the compounds of formula I as well as theracemates.

The pharmacological properties of the compounds of the invention can beillustrated by determining their capability to inhibit the specificbinding of ³ H-Oxotremorine-M (³ H-Oxo). Birdsdall N. J. M., Hulme E.C., and Burgen A. S. V. (1980). "The Character of Muscarinic Receptorsin Different Regions of the Rat Brain". Proc. Roy. Soc. London (SeriesB) 207,1.

³ H-Oxo labels muscarinic receptor in the CNS (with a preference foragonist domains of the receptors). Three different sites are labelled by³ H-Oxo. These sites have affinity of 1.8, 20 and 3000 nM, respectively.Using the present experimental conditions only the high and mediumaffinity sites are determined.

The inhibitory effects of compounds on ³ H-Oxo binding reflects theaffinity for muscarinic acetylcholine receptors.

All preparations are performed at 0°-4° C. unless otherwise indicated.Fresh cortex (0.1-1 g) from male Wistar rats (150-250 g) is homogenizedfor 5-10 s in 10 ml 20 mM Hepes pH: 7.4, with an Ultra-Turraxhomogenizer. The homogenizer is rinsed with 10 ml of buffer and thecombined suspension centrifuged for 15 min at 40,000× g. The pellet iswashed three times with buffer. In each step the pellet is homogenizedas before in 2×10 ml of buffer and centrifuged for 10 min at 40,000× g.

The final pellet is homogenized in 20 mM Hepes pH: 7.4 (100 ml per g oforiginal tissue) and used for binding assay. Aliquots of 0.5 ml is added25 μl of test solution and 25 μl of ³ H-Oxotremorine (1.0 nM, finalconcentration) mixed and incubated for 30 min at 25° C. Non-specificbinding is determined in triplicate using arecoline (1 μg/ml, finalconcentration) as the test substance. After incubation samples are added5 ml of ice-cold buffer and poured directly onto Whatman GF/C glassfibre filters under suction and immediately washed 2 times with 5 ml ofice-cold buffer. The amount of radioactivity on the filters aredetermined by conventional liquid scintillation counting. Specificbinding is total binding minus non specific binding.

Test substances are dissolved in 10 ml water (if necessary heated on asteam bath for less than 5 minutes) at a concentration of 2.2 mg/ml.25-75% inhibition of specific binding must be obtained beforecalculation of IC₅₀.

The test value will be given as IC₅₀ (the concentration (ng/ml) of thetest substance which inhibits the specific binding of ³ H-Oxo by 50%).##EQU1## where C_(o) is specific binding in control assays and C_(x) isthe specific binding in the test assay. (The calculations assume normalmass-action kinetics).

Test results obtained by testing some compounds of the present inventionwill appear from the following table 1.

                  TABLE 1    ______________________________________                 Inhibition in vitro    Compound No. OXO BINDING (ng/ml)    ______________________________________    1            0.39    2            0.47    3            1.2    4            0.43    5            0.54    6            0.33    7            1.1    8            0.44    10           1.0    11           3.2    12           7.2    13           14    14           18    15           8.2    16           5.9    17           4.9    18           6.4    20           1.8    21           3.9    22           2.1    23           2.0    24           7.9    26           10    27           5    28           1.6    29           3.0    30           5.4    31           4.3    32           0.62    33           13    34           1.6    35           5.2    36           6.4    37           4.5    38           20    39           9.2    40           2.1    41           12    43           285    44           19    45           10    47           26    49           2.1    50           0.37    51           0.47    52           1.9    53           3.8    54           0.54    55           16    56           1.0    57           1.0    58           0.6    59           3.9    61           100    62           5.4    66           2.1    67           0.30    68           0.47    69           0.43    71           1.3    72           0.92    73           19    74           2.1    ______________________________________

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, and if desired in the form of a pharmaceuticallyacceptable acid addition salt thereof, may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids, such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, in the form of suppositories forrectal administration; or in the form of sterile injectable solutionsfor parenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective muscarinic cholinergic agonistic amount of theactive ingredient commensurate with the intended daily dosage range tobe employed. Tablets containing ten (10) milligrams of the activeingredient or, more broadly, one (1) to hundred (100) milligrams, pertablet, are accordingly suitable representative unit dosage forms.

The compounds of this invention can thus be used for the formulation ofpharmaceutical preparations, e.g. for oral and parenteral administrationto mammals including humans, in accordance with conventional methods ofgalenic pharmacy.

Conventional excipients are such pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral or enteralapplication which do not deleteriously react with the active compounds.

Examples of such carriers are water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxymethyl cellulose and polyvinylpyrrolidone.

The pharmaceutical preparations can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or coloring substances and the like, which do notdeleteriously react with the active compounds.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil. Ampoules areconvenient unit dosage forms. Tablets, dragees, or capsules having talcand/or a carbohydrate carrier or binder or the like, the carrierpreferably being lactose and/or corn starch and/or potato starch, areparticularly suitable for oral application. A syrup, elixir of the likecan be used in cases where a sweetened vehicle can be employed.

Generally, the compounds of this invention are dispensed in unit formcomprising 1-100 mg in a pharmaceutically acceptable carrier per unitdosage.

The dosage of the compounds according to this invention is 1-100 mg/day,preferably 10-70 mg/day, when administered to patients, e.g. humans, asa drug.

A typical tablet which may be prepared by conventional tablettingtechniques contains:

    ______________________________________    Active compound                   5.0        mg    Lactosum       67.8       mg Ph. Eur.    Avicel ®   31.4       mg    Amberlite ®                   1.0        mg    Magnesii stearas                   0.25       mg Ph. Eur.    ______________________________________

Due to the high muscarinic cholinergic receptor agonistic activity, thecompounds of the invention are extremely useful in the treatmentsymptoms related to a reduction of the cognitive functions of the brainof mammals, when administered in an amount effective for stimulating thecognitive functions of the forebrain and hippocampus. The importantstimulating activity of the compounds of the invention includes bothactivity against the pathophysiological disease, Alzheimer's disease aswell as against normal degeneration of brain function. The compounds ofthe invention may accordingly be administered to a subject, e.g., aliving animal body, including a human, in need of stimulation of thecognitive functions of the forebrain and hippocampus, and if desired inthe form of a pharmaceutically acceptable acid addition salt thereof(such as the hydrobromide, hydrochloride, or sulfate, in any eventprepared in the usual or conventional manner, e.g., evaporation todryness of the free base in solution together with the acid), ordinarilyconcurrently, simultaneously, or together with a pharmaceuticallyacceptable carrier or diluent, especially and preferably in the form ofa pharmaceutical composition thereof, whether by oral, rectal, orparenteral (including subcutaneous) route, in an effective forebrain andhippocampus stimulating amount, and in any event an amount which iseffective for improving the cognitive function of mammals due to theirmuscarinic cholinergic receptor agonistic activity. Suitable dosageranges are 1-100 milligrams daily, 10-100 milligrams daily, andespecially 30-70 milligrams daily, depending as usual upon the exactmode of administration, form in which administered, the indicationtoward which the administration is directed, the subject involved andthe body weight of the subject involved, and the preference andexperience of the physician or veterinarian in charge.

The invention will now be described in further detail with reference tothe following examples:

EXAMPLE 1

3-(3-Chloro-1,2,5-thiadiazol-4-yl)pyridine

To a solution of sulfurmonochloride (2.4 ml, 30 mmol) inN,N-dimethylformamide (5 ml) was slowly addedalpha-aminoalpha(3-pyridyl)acetonitrile (Archive der Pharmazie 289 (4)(1956)) (1.70 g, 10 mmol). The reaction mixture was stirred at roomtemperature for 18 h. Water (20 ml) was added and the aqueous phase wasextracted with ether and the ether phase discharged. A 50% potassiumhydroxide solution was added to the aqueous phase to pH>9. The aqueousphase was extracted several times with ether and the ether phases weredried and evaporated. The residue was purified by column chromatography(SiO₂, eluent: ethyl acetate/methylene chloride (1:1)). The titlecompound was collected in 45% (880 mg) yield. M⁺ : 197.

EXAMPLE 2

A. 3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)pyridine

Sodium hydrogen sulfide monohydrate (0.25 g, 3.3 mmol) was added to asolution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3.0mmol) in DMF (20 ml) at room temperature and the reaction mixture wasstirred for 1 h. Potassium carbonate (1.24 g, 9 mmol) and6-bromocapronitrile (0.80 g, 4.5 mmol) were added and the reactionmixture was stirred for additionally 24 h. Water (50 ml) was added andextracted with ether. The combined ether phases were dried andevaporated to give the title compound.

B. 3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-(5-cyanopentylthio)-1,2,5-thiadiazol-4-yl)pyridine (3 mmol) inacetone and the reaction mixture was stirred at room temperature for 20h. and evaporated.

C.3-(3-(5-Cyanopentylthio)-1,2,5-thiadiazol4-yl)-1,2,5,6-tetrahydro-1-methylpyridinoxalate

Sodium borohydride (290 mg, 7.5 mmol) was added to a solution of3-(3-(5-cyanopentylthio)-,1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (3 mmol) in ethanol (99.9%, 20 ml) and the reaction mixture wasstirred at -10° C. for 1 h. After evaporation the residue was dissolvedin water and extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone to yield 410 mg. M.p.139°-140° C. Compound 1.

The following compounds were made in exactly the same manner, startingwith the appropriate alkyl halogenide:

3-(3-(3-Chloropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 136°-138° C. Compound 2.

3-(3-(3-Cyanopropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methlpyridineoxalate. M.p. 117.5°-118° C. Compound 3.

3-(3-(3-Phenylpropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 110°-110.5° C. Compound 4.

3-(3-(2-Phenoxyethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methlpyridineoxalate. M.p. 125.5°-126° C. Compound 5.

3-(3-(4-Cyanobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 127°-127.5° C. Compound 6.

3-(3-(8-Hydroxyoctylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 112.5°-113.5° C. Compound 7.

3-(3-(4-Chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 136°-137° C. Compound 8.

3-(3-(4,4-Bis-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 117.5°-118° C. Compound 9.

3-(3-(2-(1,3-Dioxolane-2-yl)-ethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 117°-118° C. Compound 10.

3-(3-(4-Cyanobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 138°-140° C. Compound 11.

3-(3-(2-Phenylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 155°-156° C. Compound 12.

3-(3-(4-Bromobenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 139°-140° C. Compound 13.

3-(3-(4-Methylbenzylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 162°-165° C. Compound 14.

3-(3-(4-Pyridylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 140°-142° C. Compound 15.

3-(3-(2-Benzoylethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 99°-100° C. Compound 16.

3-(3-(4-Oxo-4-(4-fluorophenyl)-butylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 131°-132° C. Compound 17.

3-(3-Benzyloxycarbonylmethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 179°-180° C. Compound 18.

3-(3-Benzylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 195°-197° C. Compound 19.

3-(3-(4,4,4-Trifluorobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 163°-165° C. Compound 20.

3-(3-(5,5,5-Trifluoropentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 134°-136° C. Compound 21.

3-(3-(6,6,6-Trifluorohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 128°-129° C. Compound 22.

3-(3-Ethoxycarbonylpentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate. M.p. 78°-81° C. Compound 23.

Example 3

A. 3-(3-(6,6,6-Trifluorohexyloxy-1,2,5-thiadiazol-4-yl)pyridine

To a mixture of sodium hydride (12.8 mmol) and 6,6,6-trifluoro-1-hexanol(3.0 g, 19.2 mmol) in tetrahydrofuran (40 ml) was added3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.3 g, 6.4 mmol). Themixture was refluxed for 36 h. and evaporated. After evaporation theresidue was dissolved in water then extracted with diethyl ether. Thedried organic phases were evaporated and the residue purified by columnchromatography (silica gel, eluent: ethyl acetate/hexanes) to yield 630mg (31%) of the title compound.

B.3-(3-(6,6,6-Trifluorohexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide

A solution of methyl iodide (852 mg, 6.0 mmol) and3-(3-(6,6,6-trifluorohexyloxy-1,2,5-thiadiazol-4-yl)pyridine (630 mg,2.0 mmol) in acetone (25 ml) was refluxed for 7 h. The solution wasevaporated and the residue was used directly in the next step.

C.1,2,5,6-Tetrahydro-1-methyl-3-(3-(6,6,6-trifluorohexyloxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate

Sodium borohydride (380 mg, 10 mmol) was added to a solution of3-(3-(6,6,6-trifluorohexyloxy-1,2,5-thiadiazol-4-yl)-1-methylpyridiniumiodide (2.0 mmol) in ethanol (15 ml) and the reaction mixture wasstirred at room temperature overnight. After evaporation the residue wasdissolved in water and extracted with diethyl ether. The dried organicphases were evaporated and the residue was purified by columnchromatography (silica gel, eluent: 25% ethyl acetate in hexanes). Thetitle compound was crystallized as the oxalate salt from acetone toyield 180 mg (21%), m.p. 138°-140° C. Theoretical %C=45.17, %H =5.21,%N=9.88. Found %C=45.13, %H=5.18, %N=9.62. Compound 24.

The following compounds were made in exactly the same manner using theappropriate alkoxy derivative:

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 130°-133° C., M⁺ : 321. Compound 25.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(4-methoxyphenyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 166°-167° C., M⁺ : 345. Compound 26.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(4-methoxyphenyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 166°-167° C., M⁺ : 331. Compound 27.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 145°-146° C., M^(+:) 306. Compound 28.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(3-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 138°-140° C., M^(+:) 306. Compound 29.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-hydroxy-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p 105°-107° C., M^(+:) 256 Compound 30.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-phenyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 146°-147° C., M⁺ : 301. Compound 31.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-thienylmethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 161°-162° C., M⁺ : 294. Compound 32.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-hydroxy-1-hexyloxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 147°-148° C., M⁺ : 297. Compound 33.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-thienylmethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 175°-176° C., M⁺ : 293. Compound 34.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-phenyl-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 136°-138° C., M⁺ : 315. Compound 35.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-pyrrolidon-1-yl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 160°-161° C., M⁺ : 322. Compound 36.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(6-acetamido-1-hexyloxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 114°-116° C., M⁺ : 338. Compound 37.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-acetamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 145°-148° C., M⁺ : 283. Compound 38.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-pyrrolidon-1-yl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p 170°-171° C., M⁺ : 309. Compound 39.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-propionamido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 148°-143° C., M⁺ : 296. Compound 40.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-oxazolidon-3-yl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 157°-159° C., M⁺ : 310. Compound 41.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-benzylthio-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 133°-134° C., M⁺ : 347. Compound 42.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(1-pyrrolidyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 141°-142° C., M⁺ : 308. Compound 43.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ureido-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate, m.p. 200° C. (decompose), M⁺ : 265. Compound 44.

1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-ethylsulfinyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate

1,2,5,6-tetrahydro-1-methyl-3-(3-(2-ethylsulfinyl-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridineoxalate was prepared in the same manner using 2-(ethylthio)ethanol asthe starting alcohol. The intermediate3-(4-(2-ethylthio-1-ethoxy)-1,2,5-thiadiazol-3-yl)pyridine was oxidizedwith 1.1 equivalent of NaIO₄ and 1 equivalent MeSO₃ H using water as thereaction solvent. After a reaction time of 3.5 h. the solution was madebasic with 2N NaOH and extracted with ethyl acetate. The combinedextracts were dried over MgSO₄ and evaporated under vacuum. Theresulting sulfoxide was then converted to the title compound in the samemanner described above. M.p. 171°-172° C., M⁺ : 302. Compound 45.

1,2,5,6-Tetrahydro-3-(3-(5-oxohexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridin

1,2,5,6-tetrahydro-3-(3-(5-hydroxyhexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridinewas prepared in the same manner using 1,5-hexandiol. Oxidation of thiscompound to the named ketone was carried out under conditions asfollows. To a -70° C. solution of oxalylchloride (420 μl, 4.8 mmol) in25 ml CH₂ Cl₂ was added DMSO (750 μl, 10.6 mmol) at a rate so as tomaintain the reaction temperature below -45° C. Two min. after theaddition1,2,5,6-tetrahydro-3-(3-(5-hydroxyhexyl)-1,2,5-thiadiazol-4-yl)-1-methylpyridine(1.3 g, 4.4 mmol) in 20 ml CH₂ Cl₂ was added slowly, keeping thetemperature below -45° C. After 15 min. Et₃ N (3 ml, 21.8 mmol) wasadded and the reaction was warmed to room temperature. Brine (50 ml) wasadded and the mixture was extracted three times with 50 ml CH₂ Cl₂. Thecombined extracts were dried over Na₂ SO₄ and evaporated under vacuum.The resulting oil was chromatographed on silica gel (90% CHCl₃, 2% MeOHas eluent), affording 810 mg of an oil, which was dissolved in MeOH andtreated with oxalic acid (250 mg, 2.8 mmol). The resulting oxalate saltwas recrystallized from MeOH/EtOAc, affording 860 mg. M.p. 143°-144° C.,M⁺ : 295. Compound 46.

EXAMPLE 4

A. Alpha-oximido-3-pyridylacetonitrile

3-pyridylacetonitrile (47.2 g, 400 mmol) was dissolved in a solution ofsodium hydroxide (16 g, 400 mmol) in methanol (100 ml). Methylnitrite,generated by dropping a solution of concentrated sulphuric acid (12.8ml) and water (26 ml) to a solution of sodium nitrite (33.2 g, 480 mmol)in water (20 ml) and methanol (20 ml), was bobbled through the3-pyridylacetonitrile solution at 0° C. The reaction mixture was stirredat 0° C. for 1 h. and the precipitate collected by filtration. Theprecipitate was washed with a little methanol to give the wanted productin 70% (41.1 g) yield. M⁺ : 147.

B. Alpha-oximino-3-pyridylacetamidoxime

A mixture of alpha-oximido-3-pyridylacetonitrile (41.0 g, 279 mmol),hydroxylamine hydrochloride (21.5 g, 310 mmol) and sodium acetate (50.8g, 620 mmol) in ethanol (99.9%, 500 ml) was refluxed for 4 h. Aftercooling, the precipitate was collected by filtration and dried. Theprecipitate contained the wanted product and sodium acetate (85 g,168%); M⁺ : 180.

C. 3-(3-amino-1,2,5-oxadiazol-4-yl)pyridine

Crude alpha-oximido-3-pyridylacetamidoxime (5 g) and phosphoruspentachloride (5 g) was refluxed in dry ether (250 ml) for 6 h. Waterand potassium carbonate to alkaline pH was added and the phasesseparated. The aqueous phase was extracted with ether and the combinedether phases dried. Evaporation of the ether phases gave the titlecompound in 850 mg yield; M⁺ : 162.

D. 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine

To a solution of 3-(3-amino-1,2,5-oxadiazol-4-yl)pyridine (1.0 g, 6.2mmol) in glacial acetic acid (16 ml) and concentrated hydrochloric acid(5.2 ml) was added CuCl₂ (938 mg, 7 mmol) and copper coils (100 mg) at0° C. After 10 min. a solution of sodium nitrite (483 mg, 7 mmol) inwater (3 ml) was added dropwise at 5° C. The reaction mixture wasstirred additionally 30 min. at 0° C. Aqueous sodium hydroxide (2N) wasadded to alkaline pH and the mixture extracted with ether. The etherphases were dried and evaporated to give a mixture of the titlecompounds. Separation by column chromatography (SiO₂, eluent: ethylacetate) gave the chloro compound, upper spot, in 230 mg yield.

E. 3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)pyridine

Sodium hydrogen sulfide monohydrate (0.74 g, 10.5 mmol) was added to asolution of 3-(3-chloro-1,2,5-oxadiazol-4-yl)pyridine (1.27, 7.0 mmol)in DMF (30 ml) at room temperature and the reaction mixture was stirredfor 1 h. Potassium carbonate (2.0 g, 14.5 mmol) and1-bromo-3-phenylpropane (2.4 g, 12 mmol) were added and the reactionmixture was stirred for additionally 24 h. Water (50 ml) was added andextracted with ether. The combined ether phases were dried andevaporated. Purification by column chromatography (SiO₂, eluent: ethylacetate/methylene chloride (1:1)) gave the title compound.

F. 3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1-methylpyridiniumiodide

Methyl iodide (1 ml, 15 mmol) was added to a solution of3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)pyridine (7 mmol) inacetone and the reaction mixture was stirred at room temperature for 20h. and evaporated.

G.3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium borohydride (650 mg, 17 mmol) was added to a solution of3-(3-(3-phenylpropylthio)-1,2,5-oxadiazol-4-yl)-1-methylpyridinum iodide(7 mmol), in ethanol (99.9%, 20 ml) and the reaction mixture was stirredat -10° C. for 1 h. After evaporation the residue was dissolved in waterand extracted with ethyl acetate. The dried organic phases wereevaporated and the residue purified by column chromatography (SiO₂,eluent: ethyl acetate/methanol (4:1)). The title compound wascrystallized as the oxalate salt from acetone and recrystallized toyield 170 mg. M.p. 106°-108° C. Compound 47.

The following compound was made in exactly the same manner using theappropriate alkylhalogenide:

3-(3-(2-phenoxyethylthio)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate, m.p. 122°-124° C. Compound 48.

EXAMPLE 5

1-(3-(3-Pyridyl)-1,2,5-thiadiazol-4-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate

To a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridine(EP 0384288) (0.43 g, 2 mmol) in DMF (30 ml) was addedsodiumhydrogensulfide (0.3 g, 4 mmol). The reaction mixture was stirredat room temperature for 1 h. Potassium carbonate (1 g) and3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-pyridine were added andthe reaction mixture stirred at room temperature overnight. Water (200ml) was added and the water phase extracted with ether (3×100 ml). Theether extracts were dried over magnesium sulfate and evaporated. Theresidue was purified by column chromatography (eluent: ethylacetate/methanol 9:1). The free base obtained was crystallized withoxalic acid from acetone in 0.9 g yield. (Compound 49). M.p. 127°-129°C.

EXAMPLE 6

1-(1-Methyltetrazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate

To a solution of 3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridine (0.30 g, 1mmol) in DMF (30 ml) were added 1-methyl-5-mercaptotetrazol (0.35 g, 3mmol) and potassium carbonate (2 g). The reaction mixture was stirred atroom temperature for 60 h. 1N hydrochloric acid was added (200 ml) andthe water phase was extracted with ether (2×100 ml). The water phase wasbasified with solid potassium carbonate and extracted with ether (3×100ml). The ether extracts from the alkaline extractions were combined anddried over magnesium sulfate. The ether phase was evaporated and theresidue was crystallized With oxalic acid from acetone giving the titlecompound in 0.4 g yield. (Compound 50). M.p. 77°-79° C.

EXAMPLE 7

The following compounds were made in exactly the same manner asdescribed in example 6 by using the reagents indicated.

1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalate from3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-methyl-5-mercapto-1,3,4-thiadiazole. (Compound 51). M.p. 102°-104°C.

1-(2-Thiazolin-2-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalatefrom3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-thiazoline-2-thiol. (Compound 52). M.p. 116°-117° C.

1-(2-Benzoxazolylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butaneoxalatefrom3-(3-(4-chlorobutylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-mercaptobenzoxazole. (Compound 53). M.p. 156°-158° C.

1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentaneoxalate from3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-methyl-5-mercapto-1,3,4-thiadiazole. (Compound 54). M.p. 69°-70°C.

1-(2-Benzthiazolylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentaneoxalate from3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-mercaptobenzthiazole. (Compound 55). M.p. 116°-117° C.

1-(1-Methyltetrazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentaneoxalate from3-(3-(5-chloropentylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 1-methyl-5-mercaptotetrazole. (Compound 56). M.p. 96°-97° C.

1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexaneoxalate from 3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-ylthio)hexaneoxalate from3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-methyl-5-mercapto-1,3,4-thiadiazole. (Compound 57). M.p. 85°-86°C.

1-(1-Methyltetrazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexaneoxalate from3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 1-methyl-5-mercaptotetrazole. (Compound 58). M.p. 65°-66° C.

1-(2-Thiazolin-2-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexaneoxalatefrom3-(3-(6-chlorohexylthio)-1,2,5-thiadiazol-4-yl)-1-methyl-1,2,5,6-tetrahydropyridineand 2-thiazoline-2-thiol. (Compound 59). M.p. 61°-62° C.

EXAMPLE 8

3-(3-Methylsulfonyl-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate hemiacetone

A solution of3-(3-methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (0.25 g, 0.0079 mmol) in H₂ O (10 ml) was cooled in an ice-waterbath as a solution of oxone (0.7 g, 0.00114 mol) in H₂ O (5 ml) wasadded dropwise. Cooling was removed and after 5 h excess NaHSO₃ wasadded. The solution was cooled in an ice-water bath, the solution madebasic, and the mixture extracted with CH₂ Cl₂ (3×25 ml). The extractswere dried, the solvent evaporated, and the residue purified by radialchromatography (5% EtOH-0.5% NH₄ OH-CHCl₃) to give a white crystallinesolid (0.2 g). The oxalate salt recrystallized from acetone to givecolorless crystals. M.p. 96°-97.5° C. (Compound 60). Analysis and NMRconfirmed that the salt contained 0.5 mol of acetone. Analysis C₉ H₁₃,N₃O₂ S-C₂ H₂ O₄ -0.5 C₃ H₆ O, C,H,N; Theory C, 39.68; H, 4.79; N, 11.10;Found C, 39.52; H, 4.85; N, 11.19.

3-(3-[2-(1-Pyrrolidinyl)ethoxy]-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridinedioxalate

A suspension of NaH (0.0075 mol) in THF (25 ml) was treated with2-hydroxyethylpyrrolidine (1 ml, 0.0086 mol) and after 30 min. the freebase of (Compound 60) (0.6 g, 0.0023 mol), was added. After anotherhour, H₂ O (2 ml) was added and the solvent evaporated. The residue wassuspended in H₂ O and extracted with CH₂ Cl₂ (3×25 ml). The extractswere dried, the solvent evaporated, and the residue purified by radialchromatography (20% EtOH-2% NH₄ OH-CHCl₃) to give a straw colored liquid(0.4 g). The dioxalate salt recrystallized from EtOH to give a whitesolid. M.p. 186°-188° C. (Compound 61). Analysis C₁₄ H₂₂,N₄ OS-2C₂ H₂O₄, C,H,N; Theory C, 45.57; H, 5.52; N, 11.81; Found C, 45.53; H, 5.50;N, 11.61.

3-(3-(3-(5-Methyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

Sodium hydride (10.2 mmol) was added to a solution of3-(5-methyl-2-thienyl)-1-propanol (4.0 g, 25.5 mmol) in THF (40 ml). Themixture was stirred for 1 h at room temperature, whereupon a solution of3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (EP 0384288) (1.0 g, 5.1mmol) in THF (10 ml) was added dropwise to the reaction mixture. Afterstirring overnight at room temperature, the reaction was quenched withwater then extracted with diethyl ether. The organic phase was driedover NaCl/Na₂ SO₄ then evaporated to yield crude3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine. Asolution of3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine (1.0 g,3.2 mmol) and iodomethane (2.3 g, 16.0 mmol) in 60 ml of acetone wasrefluxed overnight. The solution was evaporated to yield 1.5 g of thequaternized product. Sodium borohydride (0.6 g, 16.0 mmol) was carefullyadded to a solution of the quaternized product (1.5 g) in ethanol (30ml). The reaction was evaporated and the resulting residue was taken upin water and extracted with methylene chloride (3×100 ml). The organicphase was dried over NaCl/Na₂ SO₄ then evaporated. The residue waspurified by radial chromatography eluting with 0.5% NH₄ OH/5.0% EtOH inCHCl₃. The oxalate salt was made to yield 337 mg of the title compound.M.p. 134°-137° C. (Compound 62).

The following compounds were made in the same manner as described aboveusing the indicated alcohol instead of3-(5-methyl-2-thienyl)-1-propanol:

3-(3-((5-Propyl-2-thienyl)methoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 63) from (5-propyl-2-thienyl)-methanol. M.p. 134°-135°C.

3-(3-(3-(5-Pentyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 64) from 3-(5-pentyl-2-thienyl)-1-propanol. M.p.138°-140° C.

3-(3-(3-(2-Thienylthio)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 65) from 3-(2-thienylthio)-1-propanol. M.p. 102°-110°C.

EXAMPLE 10

3-(3-(3-(2-Thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate

A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (2.0 g, 10.1mmol) in DMF (10 ml) was cooled to 5° C. whereupon potassium carbonate(2.8 g, 20.2 mmol) and sodium hydrosulfide monohydrate (1.5 g, 20.2mmol) were added to the reaction. Stirred for 1 h then potassiumcarbonate (1.4 g, 10.1 mmol) and a solution of3-(2-thienyl)-1-chloro-propane (1.8 g, 11.2 mmol) in DMF (5 ml) wereadded to the reaction and stirred for 1 h at room temperature. Thereaction was quenched with water then extracted with methylene chloride(3×75 ml). The organic phase was dried over NaCl/Na₂ SO₄ thenevaporated. The residue was purified by flash chromatography elutingwith 1:1 ethyl acetate/hexanes to yield 1.0 g of3-(3-(3-(2-thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)pyridine.Quaternization and reduction was done as described in example 9.(Compound 66). M.p. 98°-100° C.

The following compounds were made in exactly the same manner asdescribed above using the indicated alkylhalogenide:

3-(3-(2-Thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 67) using (2-thienyl)-chloromethane. M.p. 131°-135° C.

3-(3-(3-(2-Oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 68) using 3-(2-oxazolidinon-3-yl)-1-chloropropane.M.p. 104°-109° C.

3-(3-(3-(2-Thiazolidinon-3-yl)-1-propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 69) using 3-(2-thiazolidinon-3-yl)-1-chloropropane.M.p. 75°-81° C.

3-(3-(5-Pentyl-2-thienyl)methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 70) using (5-pentyl-2-thienyl)chloromethane. M.p.143°-146° C.

(R)-(+)3-(3-(3-(4-Benzyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 71) using (R)3-(4-benzyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 124°-133° C.

(S)-(-)3-(3-(3-(4-Benzyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 72) using(S)-3-(4-benzyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 132°-135° C.

(4R,5S)-3-(3-(3-(4-Methyl-5-phenyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 73) using(4R,5S)-3-(4-methyl-5-phenyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p.102°-106° C.

(S)-3-(3-(3-(4-Isopropyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 74) using(S)-3-(4-isopropyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 75°-79° C.

(S)-3-(3-(3-(4-Ethyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 75) using(S)-3-(4-ethyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 69°-71° C.

(S)-3-(3-(3-(4-(2-Butyl)-2-oxazolidinon-3-yl)-1-propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 76) using(S)-3-(4-(2-butyl)-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 77°-80° C.

3-(3-(3-(4-Propyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridineoxalate (Compound 77) using3-(4-propyl-2-oxazolidinon-3-yl)-1-chloropropane. M.p. 65°-68° C.

We claim:
 1. A method for treating glaucoma, comprising administering toa subject in need thereof an effective amount of a compound of formulaI: ##STR6## wherein Z¹ is oxygen or sulphur;R¹ is hydrogen, straight orbranched C₁₋₅ -alkyl, straight or branched C₂₋₅ -alkenyl or straight orbranched C₂₋₅ -alkynyl; and R is --Z² --R² --X or --Z² --R² --Z³ --X,wherein Z² and Z³ independently are oxygen or sulphur, R² is straight orbranched C₁₋₁₅ -alkylene, straight or branched C₂₋₁₅ -alkenylene,straight or branched C₂₋₁₅ -alkynylene, each of which is optionallysubstituted with halogen, --OH, --CN, --CF₃, one or two phenyl, phenoxy,benzoyl, or benzyloxycarbonyl groups wherein each aromatic group isoptionally substituted with halogen, --CN, C₁₋₄ -alkyl or C₁₋₄ -alkoxy,and X is a heterocyclic group selected from the group consisting of1,3-dioxolanyl, pyridyl, thienyl, pyrrolidonyl, oxazolidonyl,thiazolidonyl, pyrrolidinyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,tetrazolyl, thiazolyl, oxazolyl, benzoxazolyl, and benzthiazolyl,wherein the heterocyclic group is optionally substituted at a carbon ornitrogen atom with straight or branched C₁₋₆ -alkyl, phenyl, benzyl orpyridine; or a pharmaceutically acceptable salt thereof.
 2. A methodaccording to claim 1, wherein Z¹ is sulphur.
 3. A method according toclaim 2, wherein R is --Z² --R² --X or --Z² --R² --Z³ --X, wherein Z²and Z³ independently are oxygen or sulphur, R² is straight or branchedC₁₋₁₅ -alkylene, and X is thienyl.
 4. A method according to claim 2,wherein R is --Z² --R² --X or --Z² --R² --Z³ --X, wherein Z² and Z³independently are oxygen or sulphur, R² is straight or branched C₁₋₁₅-alkylene, and X is oxazolidonyl.
 5. A method according to claim 2,wherein R is --Z² --R² --X or --Z² --R² --Z³ --X, wherein Z² and Z³independently are oxygen or sulphur, R² is straight or branched C₁₋₁₅-alkylene, and X is thiazolidonyl.
 6. A method according to claim 2,wherein R is --Z² --R² --X or --Z² --R² --Z³ --X, wherein Z² and Z³independently are oxygen or sulphur, R² is straight or branched C₁₋₁₅-alkylene, and X is 1,3,4-thiadiazolyl.
 7. A method according to claim2, wherein R is --Z² --R² --X or --Z² --R² --Z³ --X, wherein Z² and Z³independently are oxygen or sulphur, R² is straight or branched C₁₋₁₅-alkylene, and X is tetrazolyl.
 8. A method according to claim 2,wherein R is --Z² --R² --X or --Z² --R² --Z³ --X, wherein Z² and Z³independently are oxygen or sulphur, R² is straight or branched C₁₋₁₅-alkylene, and X is thiazolyl.
 9. A method according to claim 1, whereinthe compoundis:3-(3-(2-(1,3-Dioxolane-2-yl)-ethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(4-Pyridylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.
 10. A method according toclaim 1, wherein the compoundis:1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(3-thienyl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-thienylmethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-thienylmethoxy)-1,2,5-thiadiazol-4-yl)pyridine; 1.2,5,6-Tetrahydro-1-methyl-3-(3-(3-(2-pyrrolidon-1-yl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-pyrrolidon-1-yl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(2-(2-oxazolidon-3-yl)-1-ethoxy)-1,2,5-thiadiazol-4-yl)pyridine;1,2,5,6-Tetrahydro-1-methyl-3-(3-(3-(1-pyrrolidyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)pyridine;ora pharmaceutically acceptable salt thereof.
 11. A method according toclaim 26, wherein the compoundis:1-(3-(3-Pyridyl)-1,2,5-thiadiazol-4-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;1-(1-Methyltetrazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;1-(2-Thiazolin-2-ylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;1-(2-Benzoxazolylthio)-4-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)butane;1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentane;1-(2-Benzthiazolylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentane;1-(1-Methyltetrazol-5-ylthio)-5-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)pentane;1-(2-Methyl-1,3,4-thiadiazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexane;1-(1-Methyltetrazol-5-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexane;1-(2-Thiazolin-2-ylthio)-6-(3-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,2,5-thiadiazol-4-ylthio)hexane;ora pharmaceutically acceptable salt thereof.
 12. A method according toclaim 1, wherein the compoundis:3-(3-[2-(1-Pyrrolidinyl)ethoxy]-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(5-Methyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-((5-Propyl-2-thienyl)methoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(5-Pentyl-2-thienyl)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(2-Thienylthio)-1-propoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(2-Thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(2-Thienylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(2-Oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(2-Thiazolidinon-3-yl)-1-propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(5-Pentyl-2-thienyl)methylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;(R)-(+)3-(3-(3-(4-Benzyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;(S)-(-)3-(3-(3-(4-Benzyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;(4R,5S)-3-(3-(3-(4-Methyl-5-phenyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;(S)-3-(3-(3-(4-Isopropyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;(S)-3-(3-(3-(4-Ethyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;(S)-3-(3-(3-(4-(2-Butyl)-2-oxazolidinon-3-yl)-1-propylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;3-(3-(3-(4-Propyl-2-oxazolidinon-3-yl)-1-propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;ora pharmaceutically acceptable salt thereof.